Prostate cancers are characterized by progressive changes that render them increasingly aggressive, metastatic, hormone independent and resistant to treatment. The goal of this Program is to elucidate the alterations in signal transduction mechanism that underlie the progression of prostate cancer from benign, localized and androgen dependent to aggressive, disseminated and hormone independent. The Program brings together five productive and experienced investigators with important expertise relevant to the goals of this Program, three with a background in signal transduction and two with a background in prostate cancer biology and therapy. Michael J. Weber studies transducing kinase cascades regulated by Ras; Sarah J. Parsons studies signaling by protein kinases in the regulation of neuroendocrine cell growth and secretion; J. Thomas Parsons investigates integrin signaling; J. Thomas Parsons investigates integrin signaling; Charles E. Myers works on signal transduction as a therapeutic target for prostate cancer; and Leland W. K. Chung ha pioneered the development of prostate cell lines which reflect in vivo progression, and which are used by all the investigators. The Program gains from the participation of an expert Surgical Pathologist, Henry Frierson, who has begun specializing in prostate cancer and who will work with the investigators in the analysis of tissues from in vivo experiments and human samples. Project 1, J. Thomas Parsons and Leland W.K. Chung, Adhesion signaling in tumor cell progression will examine the repertoire of expressed and functional integrin molecules and the signaling pathways by which they control adhesion, motility and invasion of prostate cancer. Project 2, Michael J. Weber, Intracellular signaling and androgen independence will study the growth factor stimulated kinase cascades which can activate or bypass the androgen receptor. Project 3, Sarah J. Parsons and Charles E. Myers, Neuroendocrine cells in prostate cancer will analyze the differentiation and paracrine functions of neuroendocrine cells. Together, these projects cover critical areas which are fundamental to understanding tumor progression in prostate cancer, including events initiated at the cell surface, signals which operate intracellular and autocrine/paracrine growth regulatory products. This work should contribute significant significantly to the understanding, diagnosis, treatment and prevention of prostate cancer.